Project Summary Traumatic brain injury (TBI) causes detrimental behavioral dysfunctions and brain neurodegeneration but, unfortunately, there currently is no effective pharmaceutical TBI treatment. The underlying Phase 1 STTR grant is to develop a new class of TBI drugs that inhibit the protease cathepsin B. Genetically deleting the cathepsin B gene in mice results in substantial behavioral and pathology improvements in the controlled cortical impact (CCI) TBI model relative to animals expressing that protease. Moreover, administering tool compounds, which inhibit cathepsin B, called E64d and E64c, to wild-type mice following CCI also produce similar improvements. Cathepsin B knockout mice are healthy and prior studies in pediatric patients found E64d to be safe. Thus, there is reason to believe that cathepsin B inhibitor compounds may be effective and safe for treating TBI. The underlying grant will determine pharmacological parameters and efficacy for the tool compounds in the CCI mouse model The Grantee, American Life Science Pharmaceuticals, developed deuterium derivatives of the tool compounds and obtained patents protecting those derivatives in the United States and Europe. Those deuterium derivatives will be subsequently developed as TBI therapeutics. The instant application is for an Administrative Supplement to restore funds that were cut from the Fee category of the underlying grant due to insufficient funds at the time the award was made. The Fee category allows for unrestricted use of funds. The Supplemental Award will be used to pay for on-going patent costs in the United States and Europe. That expenditure is absolutely essential because without those patents, the TBI therapeutics cannot be commercially developed.